Regulation of Macrophages in Obesity-Enhanced Colon Cancer:Benefits of Quercetin

肥胖加剧的结肠癌中巨噬细胞的调节：槲皮素的好处

• 批准号: 8487738
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 12.25万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487738
• 关键词: Address; Adipose tissue; Adoptive Transfer; Advisory Committees; Area; Basic Science; Behavior; Biological Markers; Chronic; Clinical Research; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Commit; Committee Members; Data; Detection; Development Plans; Diagnosis; Diet; Dietary Flavonoid; Dietary Intervention; Disease; Educational workshop; Effectiveness; Environment; Epidemiologic Studies; Evaluation; Exercise Physiology; Faculty; Fatty acid glycerol esters; Flavonoids; Food; Funding; Goals; Grant; Health; Immune; Immunologic Surveillance; Immunologist; Immunology; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Investigation; Journals; K-Series Research Career Programs; Knowledge; Link; Malignant Neoplasms; Manuscripts; Mediating; Mentors; MicroRNAs; Microbiology; Modeling; Mus; Obesity; Pathology; Patients; Peer Review; Plasma; Play; Prevention; Process; Publishing; Quercetin; Regulation; Reporting; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resources; Risk; Risk Factors; Role; Signal Pathway; Source; South Carolina; Staging; Students; Techniques; Technology Transfer; Testing; Therapeutic; Toxic effect; Training; Translating; Translational Research; Tumor Tissue; Universities; Use of New Techniques; Writing; cancer therapy; career; career development; case control; clinical efficacy; colorectal cancer prevention; design; drug discovery; experience; feeding; improved; in vivo; interest; journal article; macrophage; meetings; mouse model; preclinical study; prevent; professor; programs; public health relevance; skills; symposium; tool; tumor microenvironment; tumorigenesis; working group

DESCRIPTION (provided by applicant): Dr. Angela Murphy joined the Department of Pathology, Microbiology and Immunology at the University of South Carolina as an Assistant Professor in September 2010. She is committed to a health- related research career as evident by her 40 peer-reviewed journal articles in the area of complementary and alternative (CAM) treatment approaches to infection, inflammation and cancer. Her long-term career goal is to significantly contribute to expanding global knowledge in CAM treatments for cancer. This will largely involve sustaining an independent line of translational research, engaging in cutting edge techniques, generating R01 funding, publishing in high impact journals, presentations at meetings, training students and junior faculty, technology transfer and drug discovery, as well as involvement in program projects and center grants. Her short-term goals are to expand her research and training experiences providing her with the tools to generate an independent research program and an R01 grant before the end of this proposed career development award. In the proposed investigation, Dr. Murphy will examine the role of miRNA-155 on the regulation of macrophage behavior in a mouse model of obesity-enhanced CRC, and further, whether dietary quercetin can target this process. While it is clear that she is interested in pursuing a career in CAM treatments for cancer, her current training is in Exercise Physiology. Therefore, the proposed studies will provide her with new training and expertise that she needs to become a leading immunologist with the tools to perform mechanistic and translational research on CAM in cancer. Overall, these studies will allow Dr. Murphy to gain the experience and expertise in new areas and using new techniques that will greatly enhance her ability to generate new funding, and thus, have a significant impact on the prevention of colorectal cancer. The University of South Carolina is an outstanding environment for the career development of Dr. Murphy in both successful mentors and the research resources that are available. Dr. Murphy's mentors and Advisory Committee members have a strong record of mentoring junior faculty in both basic science and clinical research in the area of CAM, inflammation and cancer. Further, the institutional research infrastructure that is available to Dr. Murphy is exceptional and will allow for successful completion of the proposed investigation. The proposed career development plan was carefully devised by Dr. Murphy and her mentors and is tailored to her ability. It focuses on five major aspects of training that she is in most need of including, 1) Meetings with Mentors and Advisory Committee Members; 2) Research Training; 3) Grant Writing; 4) Courses; and 5) Manuscript Writing. Dr. Murphy will also participate in Working Groups; Weekly Lab Meetings; Journal Club; Seminars; Workshops; and Conferences as part of the training plan. This training plan, her mentors and the research infrastructure will provide her with the necessary skills and expertise to become a highly competent independent investigator performing multidisciplinary research on CAM in cancer. A pathophysiological mechanism that may link obesity to colorectal (CRC) risk is inflammation. Adipose tissue macrophages are a primary source of inflammation; however, there has been no systematic evaluation of their regulation in obesity-enhanced CRC. miRNA-155 inhibits signaling pathways in macrophages that can suppress inflammation. It is upregulated during the macrophage inflammatory response and has been implicated in playing a role in the link between inflammation and cancer. However, there are no reports of a role of miRNA-155 in obesity-enhanced CRC. Dietary compounds are of interest given their low toxicity profiles and their ability to target inflammatio; however, there is a fundamental gap in the understanding of their effectiveness and their mechanism(s) of action. The long-term goal is to develop the flavonoid quercetin as a preventative/therapeutic strategy for obesity-enhanced CRC. The objective of this investigation is to evaluate whether macrophage-induced inflammation is regulated by miRNA-155 in obesity-enhanced CRC, and whether dietary quercetin can target this process. Further, we will begin to evaluate the clinical efficacy of miRNA-155 as a biomarker for CRC. The central hypothesis is that regulation of macrophage-induced inflammation in obesity-enhanced CRC is mediated through miRNA-155, a process that can be targeted by dietary quercetin. The rationale is that elucidating the targets of quercetin and their mechanism of action will translate to a more effective prevention/treatment approach in obesity-enhanced CRC. This hypothesis will be tested under three Specific Aims: 1) Determine the role of miRNA-155 in the regulation of macrophage-induced inflammation in obesity-enhanced CRC; 2) Evaluate whether miRNA-155 can be targeted by dietary quercetin; and 3) Determine the clinical efficacy of miRNA-155 as a biomarker for CRC. In Aim 1, we will use a miRNA-155 -/- mouse in which obesity will be induced by high fat diet (HFD) and CRC induced using AOM/DSS. We will examine inflammation and macrophage behavior in adipose tissue, immune regulation in the tumor microenvironment, and tumorigeneis. In Aim 2, we will test the hypothesis that quercetin can decrease expression of miRNA-155 in macrophages, and thus, decrease tumorigenesis in obesity-enhanced CRC. In Aim 3, we will employ a case-control design to being to determine the clinical efficacy of miRNA-155 as a biomarker for CRC, and further, assess the associations and predictive ability of miRNA-155 and advanced-stage and high-grade. The proposed investigation is significant as it addresses prevention of incidence and progression of obesity-enhanced CRC by using a dietary food component to target macrophage-induced inflammation that is thought to at the mechanistic core of this disease.

描述（由申请人提供）：安吉拉·墨菲（Angela Murphy）博士于2010年9月加入了南卡罗来纳大学的病理学，微生物学和免疫学系，担任助理教授。她致力于与健康相关的研究职业，这是她40个同伴评估的期刊在补充和替代（CAM）治疗方法中的40篇期刊文章，以供体现和替代（CAM）感染。她的长期职业目标是为扩大CAM治疗癌症的全球知识做出重大贡献。这将在很大程度上涉及维持独立的转化研究线，从事尖端技术，产生R01资金，在高影响期刊上出版，会议上的演讲，培训学生和初级教师，技术转移和药物发现，以及参与计划项目和中心侧面。她的短期目标是扩大她的研究和培训经验，从而为她提供了在该拟议的职业发展奖结束之前生成独立研究计划和R01赠款的工具。在拟议的研究中，墨菲博士将研究miRNA-155在肥胖增强的CRC小鼠模型中调节巨噬细胞行为的作用，进一步饮食槲皮素是否可以针对此过程。显然，她有兴趣从事癌症的CAM治疗职业，但她目前的培训是运动生理学。因此，拟议的研究将为她提供新的培训和专业知识，她需要通过对癌症CAM进行机械和转化研究的工具来成为领先的免疫学家。总体而言，这些研究将使墨菲博士能够在新领域获得经验和专业知识，并使用新技术可以极大地增强其产生新资金的能力，从而对预防结直肠癌产生重大影响。南卡罗来纳大学是墨菲博士在成功的导师和可用的研究资源方面的职业发展的杰出环境。墨菲博士的导师和咨询委员会成员在CAM，炎症和癌症领域的基础科学和临床研究中指导初级教师的记录有很强的记录。此外，墨菲博士可以使用的机构研究基础设施是非凡的，并且可以成功完成拟议的调查。拟议的职业发展计划是由墨菲博士和她的导师精心设计的，并为她的能力量身定制。它重点介绍了她最需要包括的五个主要方面，包括1）与导师和咨询委员会成员会面； 2）研究培训； 3）赠款写作； 4）课程； 5）手稿写作。墨菲博士还将参加工作组；每周实验室会议；期刊俱乐部；研讨会；讲习班；和会议作为培训计划的一部分。这个培训计划，她的导师和研究基础设施将为她提供 凭借必要的技能和专业知识，成为一名高度称职的独立研究者，对癌症的CAM进行多学科研究。 一种可能将肥胖与结直肠癌（CRC）风险联系起来的病理生理机制是炎症。脂肪组织巨噬细胞是炎症的主要来源。但是，在肥胖增强的CRC中没有系统地评估其调节。 miRNA-155抑制巨噬细胞中可以抑制炎症的信号通路。它在巨噬细胞炎症反应期间被上调，并与在炎症与癌症之间的联系中发挥作用。但是，没有关于miRNA-155在肥胖增强CRC中的作用的报道。鉴于其低毒性谱及其靶向炎症的能力，饮食化合物令人感兴趣。但是，理解其有效性和作用机制存在根本的差距。长期目标是开发类黄酮槲皮素作为肥胖增强CRC的预防/治疗策略。这项研究的目的是评估巨噬细胞诱导的炎症是否受肥胖增强的CRC的miRNA-155调节，以及饮食槲皮素是否可以针对此过程。此外，我们将开始评估miRNA-155作为CRC生物标志物的临床疗效。中心假设是，通过miRNA-155介导了巨噬细胞诱导的巨噬细胞诱导的炎症，这一过程可以由膳食槲皮素靶向。理由是阐明槲皮素的靶标及其作用机理将转化为肥胖增强的CRC中更有效的预防/治疗方法。该假设将在三个具体目的下进行检验：1）确定miRNA-155在肥胖增强的CRC中巨噬细胞诱导的炎症调节中的作用； 2）评估miRNA-155是否可以用膳食槲皮素靶向； 3）确定miRNA-155作为CRC的生物标志物的临床疗效。在AIM 1中，我们将使用miRNA-155 - / - 小鼠，其中肥胖症将由高脂饮食（HFD）和使用AOM/DSS诱导的CRC诱导。我们将检查脂肪组织中的炎症和巨噬细胞行为，肿瘤微环境中的免疫调节和肿瘤。在AIM 2中，我们将检验以下假设：槲皮素可以降低巨噬细胞中miRNA-155的表达，从而减少肥胖增强的CRC中的肿瘤发生。在AIM 3中，我们将采用病例对照设计来确定miRNA-155作为CRC的生物标志物的临床疗效，并进一步评估miRNA-155和高级阶段和高级阶段的关联和预测能力。提出的研究很重要，因为它通过使用饮食中的食物成分来靶向巨噬细胞诱导的炎症，以解决肥胖增强CRC的发病率和进展，这被认为是这种疾病的机械核心。